An Efficacy and Safety Trial of Verubecestat (MK-8931) in Mild to Moderate Alzheimer's Disease (P07738) (EPOCH)

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Key information relevant to the recruitment process for the
overall study, such as dates of the recruitment period and locations

Part I began by enrolling approximately 50 participants per arm (200 total). Enrollment continued until the first 200 participants reached 13 weeks treatment; total enrollment at that time: ~400. For these ~400 participants (Safety Cohort), an interim analysis (IA) was conducted to assess safety. Following IA, enrollment continued (Main Cohort).

Pre-Assignment Details

Significant events and approaches for the overall study
following participant enrollment, but prior to group assignment

2211 participants were randomized in Part I, with 2210 receiving treatment. As planned per protocol, no participants were randomized to the Verubecestat 60 mg arm (Arm C) in the Main Cohort. Participants completing Part I were eligible to continue to Part II. The trial was terminated early and did not complete as planned.

Reporting Groups

Description

Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]

[Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.

Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]

[Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]

[Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]

[Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

Participant Flow for 2 periods

Period 1: Part I (Base Study)

Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]

Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]

Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]

Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]

STARTED

703

700

103

705

Treated

702

700

103

705

COMPLETED

501

497

77

516

NOT COMPLETED

202

203

26

189

Adverse Event

41

52

8

33

Death

10

7

2

8

Lack of Efficacy

3

8

0

7

Lost to Follow-up

4

2

4

4

Non-Compliance with Study Drug

3

2

0

0

Physician Decision

10

7

1

4

Protocol Violation

2

0

1

2

Screen Failure

2

0

0

0

Site Discontinued Study Participation

1

3

0

0

Study Terminated by Sponsor

72

73

0

86

Participant Moved

4

3

1

7

Trial Partner/Caregiver Withdrew Consent

27

25

2

18

Withdrawal by Subject

23

21

7

20

Period 2: Part II (Extension Study)

Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]

Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]

Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]

Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]

STARTED

379 [1]

366 [1]

61 [1]

396 [1]

Treated

379

365

61

394

COMPLETED

0

0

0

0

NOT COMPLETED

379

366

61

396

Adverse Event

10

11

7

26

Death

3

3

2

6

Lack of Efficacy

1

5

0

1

Lost to Follow-up

3

4

0

1

Non-Compliance with Study Drug

0

0

0

1

Physician Decision

7

11

6

12

Study Terminated by Sponsor

329

315

34

323

Participant Moved

3

3

0

3

Trial Partner/Caregiver Withdrew Consent

18

12

8

16

Withdrawal by Subject

5

2

4

7

[1]

Number started refers only to participants completing Part I, volunteering to continue to Part II.

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

All randomized participants in Study Part I (Base Study)

Reporting Groups

Description

Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]

[Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.

Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]

[Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]

[Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]

[Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. Lower scores indicate less independence in activity performance.

[2]

All randomized participants (Part I) with a baseline and ≥1 within-analysis-window observation for ADCS-ADL subsequent to ≥1 dose of study drug (FAS population).

The CDR-SB score is a clinical rating of global cognitive function, comprised of 6 domains including: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant’s caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores sum to the total CDR-SB score, with total scores ranging from 0-18. Higher scores indicate more severe cognitive impairment.

[2]

All randomized participants (Part I) with a baseline and ≥1 within-analysis-window observation for CDR-SB subsequent to ≥1 dose of study drug (FAS population).

Total Tau concentration in the cerebrospinal fluid (CSF) was monitored as a measure of brain tau pathology.

[2]

All randomized participants (Part I) with a baseline and ≥1 within-analysis-window observation for CSF Total Tau subsequent to ≥1 dose of study drug (FAS population). Per protocol, CSF Total Tau concentration was analyzed as part of a substudy in Part I, with testing occurring at select trial sites.

All randomized participants with a baseline and ≥1 within-analysis-window SUVR observation subsequent to ≥1 dose of study drug (FAS population). SUVR testing occurred at select sites as a Part I substudy. Per protocol, SUVR was not analyzed for the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat.

NPI is a clinical assessment of psychiatric status, covering 12 domains. Based on an interview of the participant’s caregiver, each domain is assessed for symptom frequency [range: 1 (occasional) to 4 (very frequent)] and severity [range: 1 (mild) to 3 (severe)]. Domain scores [range: 0 to 12] are calculated as the product of the frequency and severity scores (i.e. frequency x severity); if no symptoms are present, domain score is 0. The 12 domain scores sum to a total NPI score [range: 0 (no symptoms in any domain) to 144]. Higher scores reflect more severe psychiatric impairment.

The MMSE is a cognitive assessment of 5 domains including: orientation; attention; memory; language; and constructional praxis. These domains are assessed with 11 total questions related to the participant. Participants are scored based on the number of correct responses; depending on the question, potential scores range from 0 (no correct response) to either 1 (4 questions), 2 (1 question), 3 (3 questions), or 5 (3 questions). Scores from each question are summed to the total MMSE score, with total scores ranging from 0-30. Higher scores indicate better cognitive performance.

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts
the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release
and can embargo communications regarding trial results for a period that is less than or equal to 60 days.
The sponsor cannot require changes to the communication and cannot extend the embargo.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release
and can embargo communications regarding trial results for a period that is more than 60 days but less than
or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Restriction Description:
The investigator agrees to provide to the sponsor, 45 days prior to submission for publication or presentation, review copies of abstracts or manuscripts for publication that report any results of the trial. The sponsor shall have the right to review and comment with respect to publications, abstracts, slides, and manuscripts and the right to review and comment on the data analysis and presentation.